Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Daniel J. Weiner, Emilie M. Wigdor, Stephan Ripke, Raymond K. Walters, Jack A. Kosmicki, Jakob Grove, Kaitlin E. Samocha, Jacqueline I. Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M. Hougaard, Jacob Taylor, David Skuse, Bernie Devlin, Richard Anney, Stephan J. Sanders, Somer Bishop, Preben Bo Mortensen, Anders D. BørglumGeorge Davey Smith, Mark J. Daly, Elise B. Robinson, Marie Bækvad-Hansen, Ashley Dumont, Christine Hansen, Thomas F. Hansen, Daniel Howrigan, Manuel Mattheisen, Jennifer Moran, Ole Mors, Merete Nordentoft, Bent Nørgaard-Pedersen, Timothy Poterba, Jesper Poulsen, Christine Stevens, Verneri Anttila, Peter Holmans, Hailiang Huang, Lambertus Klei, Phil H. Lee, Sarah E. Medland, Benjamin Neale, Lauren A. Weiss, Lonnie Zwaigenbaum, Timothy W. Yu, Kerstin Wittemeyer, A. Jeremy Willsey, Ellen M. Wijsman, Suma Jacob, Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group

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289 Scopus citations


Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

Original languageEnglish (US)
Pages (from-to)978-985
Number of pages8
JournalNature Genetics
Issue number7
StatePublished - Jul 1 2017

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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.


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